| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human epidermal growth factor receptor 2 (HER2)-positive Early Breast Cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2-positive breast cancer refers to breast cancer that is positive for the HER2 protein, which promotes the growth of cancer cells |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| • To demonstrate the non-inferiority of the Cycle 7 (pre-dose Cycle 8) serum pertuzumab Ctrough of pertuzumab subcutaneous (SC) within the fixed-dose combination (FDC) compared with Perjeta IV (intravenous). |
|
| E.2.2 | Secondary objectives of the trial |
• To demonstrate the non-inferiority of the Cycle 7 (pre-dose Cycle 8) serum trastuzumab Ctrough of trastuzumab SC within the FDC compared with Herceptin IV
• To evaluate the efficacy of the SC FDC of pertuzumab and trastuzumab + chemotherapy compared with Perjeta IV and Herceptin IV + chemotherapy based on total pathological complete response
• To evaluate the efficacy of the SC FDC of pertuzumab and trastuzumab + chemotherapy compared with Perjeta IV and Herceptin IV + chemotherapy based on invasive disease-free survival ( including and excluding second primary non-breast cancer), event free survival (including and excluding second primary non-breast cancer), distant recurrence-free interval and overall survival
• To evaluate the safety of the SC FDC of pertuzumab and trastuzumab compared with Perjeta IV and Herceptin IV |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age >= 18 years
- Ability to comply with the study protocol, in the investigator’s judgment
- Eastern Cooperative Oncology Group Performance Status <= 1
- Female and male patients with Stage II - IIIC (T2-T4, plus any N, or any T plus N1- 3, M0), locally advanced, inflammatory, or early-stage, unilateral, and histologically confirmed invasive breast cancer
- Primary tumor > 2 cm in diameter, or node-positive disease
- HER2-positive breast cancer confirmed by a central laboratory prior to study enrollment. HER2-positive status will be determined based on pretreatment breast biopsy material
- Hormone receptor status of the primary tumor, centrally confirmed
- Patient agreement to undergo mastectomy or breast conserving surgery after neoadjuvant therapy
- Availability of formalin-fixed, paraffin-embedded tumor tissue block for central confirmation of HER2 and hormone receptor status and additional biomarker research
- Baseline left ventricular ejection fraction (LVEF) >= 55% measured by echocardiogram or multiple-gated acquisition scan
- For women of childbearing potential (WOCBP) who are sexually active: agreement to remain abstinent or use one highly effective non-hormonal contraceptive method with a failure rate of < 1% per year, or two effective non-hormonal contraceptive methods during the treatment period and for 7 months after the last dose of HER2-targeted therapy, and agreement to refrain from donating eggs during this same period
- For men: men must remain abstinent or use a condom with a spermicidal product during the treatment
period and for 7 months after the last dose of HER2-targeted therapy to avoid exposing the embryo. Men must refrain from donating sperm during this same period
- A negative serum pregnancy test must be available prior to randomization for WOCBP, unless they have undergone surgical sterilization
- No major surgical procedure unrelated to breast cancer within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
|
|
| E.4 | Principal exclusion criteria |
- Stage IV breast cancer
- Patients with a history of invasive breast cancer
- Patients with a history of concurrent or previously treated non-breast malignancies except for appropriately treated 1) non-melanoma skin cancer and/or 2) in situ carcinomas, including cervix, colon, and skin
- Patients who have received any previous systemic therapy for treatment or prevention of breast cancer, or radiation therapy for treatment of cancer
- Patients who have a past history of ductal carcinoma in situ or lobular carcinoma in situ if they have received any systemic therapy for its treatment or radiation therapy to the ipsilateral breast
- Patients with high-risk for breast cancer who have received chemo preventative drugs in the past are not allowed to enter the study
- Patients with multi-centric breast cancer, unless all tumors are HER2-positive
- Patients with bilateral breast cancer
- Patients who have undergone an excisional biopsy of primary tumor and/or axillary lymph nodes
- Axillary lymph node dissection prior to initiation of neoadjuvant therapy
- Sentinel lymph node biopsy prior to neoadjuvant therapy
- Treatment with any investigational drug within 28 days prior to randomization
- Serious cardiac illness or medical conditions
- Inadequate bone marrow function, renal function or impaired liver function
- Current severe, uncontrolled systemic disease that may interfere with planned treatment
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 7 months after the last dose of HER2-targeted therapy
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator’s judgment, precludes the patient’s safe participation in and completion of the study
- Known active liver disease, for example, active viral hepatitis infection, autoimmune hepatic disorders, or sclerosing cholangitis
- Concurrent, serious, uncontrolled infections, or known infection with HIV
- Known hypersensitivity to study drugs, excipients, and/or murine proteins
- Current chronic daily treatment with corticosteroids
- History of other malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, colon, skin, and/or non-melanoma skin carcinoma.
- History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease, coronary heart disease, clinically significant electrolyte abnormalities, or family history of sudden unexplained death or long QT syndrome |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1. Serum pertuzumab Ctrough during Cycle 7 (pre-dose Cycle 8). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Serum trastuzumab Ctrough during Cycle 7 (pre-dose Cycle 8)
2. Total pathological complete response (ypT0/isypN0)
3. Invasive disease-free survival (including and excluding second primary non-breast cancer)
4. Event free survival (including and excluding second primary non-breast cancer)
5. Distant recurrence-free interval
6. Overall survival
7. Incidence and severity of adverse events and serious adverse events, with severity determined according to National Cancer Institute Common Terminology Criteria for Adverse Events version4 (NCI CTCAE v4)
8. Laboratory test abnormalities according to NCI CTCAE v4
9. Incidence of a symptomatic ejection fraction decrease (“Heart failure”) of New York Heart Association (NYHA) Class III or IV and a drop in LVEF of at least 10-percentage points from baseline and to below 50%
10. Cardiac death
11. Incidence of an asymptomatic or mildly symptomatic left ventricular systolic dysfunction of NYHA Class II, defined as an LVEF decrease of at least 10-percentage points below the baseline measurement to an absolute LVEF value of <50% |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Pre-dose at Cycle 8
2-11. Up to 5.5 years
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 66 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Brazil |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| Taiwan |
| Turkey |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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